The therapeutic mechanism of action of antidepressant medications in humans remains unknown. Comparison of effects on specific neurotransmitters and their metabolites in cerebrospinal fluid (CSF), plasma and urine in the same patients continues. Findings of special interest during the last year include the following: 1. Unique effects of electroconvulsive therapy (ECT) in humans continue to emerge: unlike all antidepressant drugs studied it does not reduce whole body norepinephrine (NE) turnover as measured in urine or NE and serotonin turnover as measured by MHPG and 5HIAA, respectively, in CSF. In fact ECT increases both 5HIAA and the dopamine (DA) metabolite, HVA in CSF. 2. Based on these clinical findings we carried out experiments on ECT in rats and found a selective increase in the D1 subtype of DA receptor in substantial nigra and caudate. Since ECT has been reported to have therapeutic effects in mania, psychosis and Parkinsonism as well as depression these DA effects likely have clinical and mechanistic implications. 3. In keeping with the theme that more than one neurotransmitter change is involved in antidepressant action, we have found that drugs with specific classes of initial biochemical effects have unique in vivo profiles of effects in humans only when changes of MHPG, 5HIAA and HVA are simultaneously taken into account. We have employed a 3-dimensional graph to obtain clear discrimination between five classes of drugs using these amine metabolites. 4. Alprazolam, a potent anti-anxiety agent with possible antidepressant properties, produces unusually robust decreases of ACTH and cortisol following intravenous administration. This finding may provide for a new test for the responsivity of the HPA axis; i.e. is it more difficult to suppress in certain psychiatric illnesses?